Establishing a Design Blueprint for Nanomedicines for Oral Drug Delivery

到目前为止，口服给药是最受欢迎的服药方式。其他给药途径与患者可接受性和依从性降低以及疼痛、高成本和风险（例如注射）有关。患者对口服给药的偏好反映在药物开发过程中，因此一种新的药物化合物几乎总是以口服给药为目标（局部治疗的药物，如治疗皮肤病的药膏和治疗哮喘的吸入剂除外）。然而，目前还不可能通过口服途径给药。这在很大程度上是因为一些药物1)容易在胃环境中降解，2)通过肠壁的水平不足以显示临床益处（药物需要进入血液才能发挥全身治疗作用）。一个很好的例子是胰岛素：需要胰岛素治疗的患者通常需要每天注射2-5次作为终身治疗。该项目的目标是建立一个工程药物载体的设计蓝图，以实现或改善口服药物输送。本项目考虑的药物载体是基于极小的颗粒（直径相当于人类头发厚度的1/1000）或纳米颗粒，它们能够穿过肠上皮，携带药物穿过肠壁。以前就有人提出使用纳米颗粒来实现口服给药。然而，一个关键的问题是，纳米颗粒，类似于一些药物，如胰岛素和基于抗体的药物，不容易穿过肠壁或上皮。这是因为肠上皮的解剖结构，它由一层紧密堆积和相互连接的细胞组成，形成一个栅栏，为物质从肠腔向血液的运动提供了一个强大的屏障。该项目的核心是合理设计和制造易于穿过肠上皮的纳米颗粒。为此，我们将首先创造一些化合物（肽），旨在通过通常运输生物分子的受体穿过肠组织屏障（上皮）。然后，我们将不同数量的“转运肽”附着在不同大小的纳米颗粒表面。所产生的系统将在基于实验室培养的人类肠上皮细胞的肠道模型中进行评估，模拟肠道组织。在之前的工作中，申请人已经确定了一些支持当前应用的关键技术进步。因此，拟议的项目是基于申请人的长期努力（包括与当前提案相关的先前工作）来改善口服给药。我们将根据以往的经验和初步数据，使用合理的设计方法，创建多个不同的系统，并以稳健的方式对它们进行测试。这将使我们能够识别“装饰”有运输能力的肽的纳米颗粒，这些肽很容易穿过肠道组织屏障。这些系统的特性（例如纳米颗粒的大小和运输激活肽的特性）使其能够通过肠道组织进行运输，这将导致纳米颗粒的设计蓝图，这些纳米颗粒具有携带药物货物穿过肠壁的能力，从而使目前无法通过这种途径服用的药物能够口服给药。

Oral administration is by far the most preferred way of taking medicines. Other drug administration routes are associated with decreased patient acceptability and compliance, as well as pain, high costs and risks (e.g. injections). Patient preference for oral administration is reflected in drug development processes, whereby a new drug compound is almost always aimed for oral delivery (exceptions exist in the case of drugs for local treatment such as creams for skin conditions and inhalers for asthma). However, currently it is not possible to deliver all drugs through the oral route. This is largely because some drugs are 1) prone to degradation in the stomach environment and 2) do not cross the intestinal wall in sufficient levels to show clinical benefit (drugs need to be in the blood to exert systemic therapeutic effect). A good example is insulin: patients requiring insulin therapy usually need between 2-5 injections per day as lifelong therapy. This project's ambition is to establish a design blueprint for engineering drug carriers that enable or improve oral drug delivery. Drug carriers considered in this project are based on extremely small particles (diameters equivalent to 1/1000th of the thickness of a human hair) or nanoparticles with the ability to cross the intestinal epithelium, carrying the drug cargo across the intestinal wall.The use of nanoparticles to enable oral drug delivery has been proposed before. However, a key problem is that nanoparticles, similarly to some drugs such as insulin and antibody-based medicines, do not readily cross the intestinal wall or epithelium. This is because of the anatomy of the intestinal epithelium, which consists of a layer of closely packed and interconnected cells forming a fence which presents a formidable barrier to the movement of material from the intestinal lumen to blood. Central to this project is rational design and fabrication of nanoparticles that readily cross the intestinal epithelium. To this end, we will first create a number of compounds (peptides) designed to cross the intestinal tissue barrier (epithelium) through receptors that normally transport biological molecules. We will then attach these 'transport enabling peptides' in varying amounts to the surface of nanoparticles of different size. The resulting systems will be evaluated in an intestinal model based on human intestinal epithelium cells grown in the lab, mimicking the intestinal tissue. In previous work the applicant has identified a number of key technological advances that underpin the current application. The proposed project is therefore based on the applicant's long-standing efforts - including prior work pertinent to the current proposal - to improve oral drug delivery. We will create a number of different systems, using a rational design approach based on previous experience and preliminary data, and test them in a robust way. This will enable us to identify nanoparticles 'decorated' with transport enabling peptides that readily cross the intestinal tissue barrier. The characteristics of these systems (e.g. nanoparticle size and identity of transport enabling peptide) that enable transport across the intestinal tissue will result in a design blueprint for nanoparticles with the ability to carry drug cargo across the intestinal wall, enabling oral administration of drugs that currently cannot be taken by this route.